Coagulase-negative staphylococci (CoNS) are primarily commensals residing on the skin and mucosa of humans and animals. This chapter summarizes the most recent findings in the genomics of CoNS and discusses the mechanisms and factors contributing to the extraordinary flexibility of these pathogens. It first discusses fitness and virulence-associated factors of CoNS. All CoNS were found to be devoid of superantigen and toxin genes, but a number of genes and factors were identified which are associated with the commensal lifestyle and also the virulence of CoNS. An interesting finding of CoNS sequencing projects was that many of the species-and virulence-specific genes are located in a certain region of the staphylococcal genome around the chromosomal origin of replication. CoNS harbor a great diversity of mobile genetic elements which comprise, in addition to plasmids, mainly bacteriophages, genomic islands, transposons, and insertion sequence elements (IS). Horizontal gene transfer by mobile genetic elements has a major impact on enhancing the biological fitness of CoNS. Biofilm formation is a major pathomechanism of CoNS, notably in Staphylococcus epidermidis. Different mechanisms to modulate biofilm formation are indeed detectable during CoNS infections, and the process is therefore supposed to be critically involved in the establishment of device-associated S. epidermidis infections. In most cases, hypervariability of biofilm formation was detected which was also accompanied by genome rearrangements, reflecting a significant flexibility of the staphylococcal genome during the infection process.